This application is the National Stage of International Application No. PCT/JP99/05469, filed on Oct. 5, 1999.
The present invention relates to novel condensed pyridazine derivatives exhibiting an excellent anti-allergic, anti-histaminic, anti-inflammatory or eosinophil chemotaxis-inhibiting activity, or other activities, and useful as agents for preventing or treating atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria, etc., their pro-drugs, methods of their production, and their use in medicaments.
A large number of compounds with a condensed pyridazine skeleton are currently synthesized as drugs for a variety of diseases. For example, U.S. Pat. No. 3,915,968 discloses a compound represented by the formula: 
wherein R and R3 independently represent a hydrogen atom or a lower alkyl group (at least one of R and R3 is a lower alkyl group); R1 and R2 represent a heterocyclic group selected from the group consisting of pyrrolidine, piperidine, piperazine and morpholine taken together with the adjacent nitrogen atom; or a salt thereof. U.S. Pat. No. 4,136,182 discloses that a compound represented by the formula: 
wherein R represents a hydrogen atom, a phenyl group or a lower alkylcarbonylamino group; R1 represents morpholino or piperidino; R2 represents a hydrogen atom or a lower alkyl group (at least one of R and R2 is a group other than a hydrogen atom; when R is a phenyl group, R1 is morpholino and R2 is a lower alkyl group); or a salt thereof, is useful as a bronchodilator for mitigating bronchial spasms.
Also, Japanese Patent Unexamined Publication No. 279447/1994 discloses that a compound represented by the formula: 
wherein R1 represents a hydrogen atom, a lower alkyl group that may be substituted, or a halogen atom; R2 and R3 independently represent a hydrogen atom or a lower alkyl optionally having a substituent, or may form a 5- to 7-membered ring with the adjacent xe2x80x94Cxe2x95x90Cxe2x80x94; X represents an oxygen atom or S(O)p (p represents an integer from 0 to 2); Y represents a group represented by the formula: 
(R4 and R5 independently represent a hydrogen atom or a lower alkyl group optionally having a substituent) or a divalent group derived from a 3- to 7-membered homocycle or heterocycle optionally having a substituent; R6 and R7 independently represent a hydrogen atom, a lower alkyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, or an aryl group that may be substituted, or may form a nitrogen-containing heterocyclic group optionally having a substituent, with the adjacent nitrogen atom; m represents an integer from 0 to 4, and n represents an integer from 0 to 4; or a salt thereof; and, as an example synthetic product, a compound of the formula: 
exhibits anti-asthmatic, anti-PAF, anti-inflammatory and anti-allergic activities.
Furthermore, Japanese Patent Unexamined Publication No. 279446/1994 describes a compound represented by the formula: 
wherein R1 represents a hydrogen atom, a lower alkyl group optionally having a substituent, or a halogen atom; R2 and R3 independently represent a hydrogen atom or a lower alkyl group optionally having a substituent (provided that either of R2 and R3 is a hydrogen atom, the other represents a lower alkyl group optionally having a substituent), or may form a 5- to 7-membered ring taken together with the adjacent xe2x80x94Cxe2x95x90Cxe2x80x94; X represents an oxygen atom or S(O)p (p represents an integer from 0 to 2); Y represents a group represented by the formula: 
(R4 and R5 independently represent a hydrogen atom or a lower alkyl group optionally having a substituent) or a divalent group derived from a 3- to 7-membered homocycle or heterocycle optionally having a substituent; R6 and R7 independently represent a hydrogen atom, a lower alkyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, or an aryl group optionally having a substituent, or may form a nitrogen-containing heterocyclic group optionally having a substituent, taken together with the adjacent nitrogen atom; m represents an integer from 0 to 4, and n represents an integer from 0 to 4; or a salt thereof; and discloses that these compounds possess anti-allergic, anti-inflammatory and anti-PAF (platelet activating factor) activities to suppress bronchial spasms and bronchial contraction, and can be used as effective anti-asthmatic agents.
On the other hand, as compounds possessing anti-allergic or anti-histaminic activities, there may be mentioned, for example, terfenadine (The Merck Index, 12th edition, 9307) and ebastine (The Merck Index, 12th edition, 3534), which are already in clinical use.
In addition, EP128536 discloses anti-bacterial compounds represented by the formula: 
and so on, and U.S. Pat. No. 4,499,088 discloses anti-bacterial compounds represented by the formula: 
and so on. However, no description is given about anti-allergic activity, anti-histaminic activity, anti-inflammatory activity and so on.
There is demand for the development of novel compounds more satisfactory than conventional anti-allergic agents, anti-histaminic agents, anti-inflammatory agents etc. in terms of activity efficacy, sustained activity, safety etc.
After various extensive investigations to resolve the above problems, the present inventors synthesized for the first time (1) a novel condensed pyridazine compound, owing to its unique chemical structure characterized by the presence of substituted piperidine or piperazine via a spacer from the 6-position of the triazolo[4,3-b]pyridazine skeleton, or a salt thereof, and (2) a novel condensed pyridazine compound, owing to its unique chemical structure characterized by the presence of substituted piperidine or piperazine via a spacer from the 6-position of the [1,2,4]triazolone[4,3-b]pyridazine skeleton, or a salt thereof, and found that these compounds exhibit unexpectedly excellent anti-allergic, anti-histaminic, anti-inflammatory, eosinophil chemotaxis-inhibiting activity, and excellent sustained activity and safety, based on their unique chemical structures, and are useful as preventive or therapeutic agents for atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria, etc., based on these pharmacological activities. The inventors conducted further investigations based on these findings, and developed the present invention.
The present invention provides:
(1) A compound represented by the formula: 
wherein Ring A is a ring represented by the formula: 
(wherein R1a is a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group having a substituent; R1b is a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group optionally having a substituent); Ar1 and Ar2 are independently an aromatic group optionally having a substituent, and may form a condensed ring group with an adjacent carbon atom; Ring B is a nitrogen-containing heterocycle optionally having a substituent; X and Y, whether identical or not, are a bond, an oxygen atom, S(O)p (p is an integer from 0 to 2), NR4 wherein R4 is a hydrogen atom or a lower alkyl group, or a divalent linear lower hydrocarbon group which may have a substituent, and which may contain 1 to 3 hetero atoms; R2 and R3, whether identical or not, are a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group optionally having a substituent; R7 is a hydrogen atom, a hydroxy group which may be substituted by lower alkyl or a carboxyl group; provided that Ring B is not a heterocycle represented by the formula: 
wherein r is 0 or 1, or a salt thereof,
(2) A compound as defined in term (1) wherein Ar1 and Ar2 are independently an aromatic hydrocarbon group optionally having a substituent,
(3) A compound as defined in term (1) wherein Ar1 and Ar2 are independently a phenyl group optionally having a substituent,
(4) A compound as defined in term (1) wherein Ar1 and Ar2 are independently
(1) a phenyl group which may be substituted by a halogen atom or C1-6 alkyl, or
(2) a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from among a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms,
(5) A compound as defined in term (1) wherein Ring B is a ring represented by the formula: 
wherein Z is a nitrogen atom or a methine group, Z1 and Z2 are independently a linear C1-4 alkylene group which may be substituted by a hydroxy group, an oxo group or a C1-6 alkyl group,
(6) A compound as defined in term (1) wherein X is a bond, an oxygen atom or NH,
(7) A compound as defined in term (1) wherein Y is
(i) a C1-6 alkylene group,
or a group represented by the formula:
(ii) xe2x80x94(CH2)p Oxe2x80x94,
(iii) xe2x80x94(CH2)p1NHxe2x80x94,
(iv) xe2x80x94(CH2)p1Sxe2x80x94,
(v) xe2x80x94(CH2)q1CH(OH)(CH2)q2Oxe2x80x94,
(vi) xe2x80x94(CH2)q1CH(OH)(CH2)q2NHxe2x80x94,
(vii) xe2x80x94(CH2)q1CH(OH)(CH2)q2Sxe2x80x94,
(viii) xe2x80x94(CH2)p1CONHxe2x80x94,
(ix) xe2x80x94COO(CH2)p1Oxe2x80x94,
(x) xe2x80x94COO(CH2)p1NHxe2x80x94,
(xi) xe2x80x94COO(CH2)p1Sxe2x80x94,
(xii) xe2x80x94(CH2)q1O(CH2)q2Oxe2x80x94,
(xiii) xe2x80x94(CH2)q1O(CH2)q2NHxe2x80x94 or
(xiv) xe2x80x94(CH2)q1O(CH2)q2Sxe2x80x94 wherein p1 is an integer from 1 to 6, q1 and q2 are independently an integer from 1 to 3,
(8) A compound as defined in term (1) wherein Y is a group represented by the formula:
xe2x80x94(CH2)m-Y1xe2x80x94(CH2)n-Y2xe2x80x94
wherein Y1 and Y2 are independently a bond, an oxygen atom, S(O)p (p is an integer from 0 to 2), NR4 (R4 is a hydrogen atom or a lower alkyl group), a carbonyl group, a carbonyloxy group or a group represented by the formula: 
wherein R5 and R6, whether identical or not, are a hydroxy group or a C1-4 alkyl group; m and n are independently an integer from 0 to 4 (sum of m and n is not more than 6),
(9) A compound as defined in term (1) wherein R1a is
(1) a hydrogen atom,
(2) a carboxyl group,
(3) a C1-6 alkoxy-carbonyl group,
(4) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C1-6 alkoxy-carbonyl and (iv) carbamoyl, or
(5) a carbamoyl group which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl,
(10) A compound as defined in term (1) wherein R1b is
(1) a hydrogen atom, or
(2) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C1-6 alkoxy-carbonyl, (iii) C1-6 alkyl-carbonyloxy and (iv) C1-6 alkyl-carbonyloxy-C1-6 alkoxy-carbonyl,
(11) A compound as defined in term (1) wherein R2 and R3 are a hydrogen atom,
(12) A compound as defined in term (1) wherein R7 is a hydrogen atom or a hydroxy group,
(13) A compound as defined in term (1) wherein Ar1 and Ar2 are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula: 
X is a bond or an oxygen atom;
Y is a group represented by the formula:
xe2x80x94(CH2)m-Y3xe2x80x94(CH2)n-Y4xe2x80x94
xe2x80x83wherein Y3 is a bond or xe2x80x94CH(OH)xe2x80x94, Y4 is an oxygen atom, S or NH, and m and n are independently an integer from 0 to 6 (sum of m and n is not more than 6);
R1a is
(1) a hydrogen atom,
(2) a carboxyl group,
(3) a C1-6 alkoxy-carbonyl group,
(4) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C1-6 alkoxy-carbonyl and (iv) carbamoyl, or
(5) a carbamoyl group which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl;
R1b is
(1) a hydrogen atom, or
(2) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C1-6 alkoxy-carbonyl, (iii) C1-6 alkyl-carbonyloxy and (iv) C1-6 alkyl-carbonyloxy-C1-6 alkoxy-carbonyl;
R2, R3 and R7 are a hydrogen atom,
(14) A compound represented by the formula: 
wherein the symbols have the same definitions as those shown in term (1), or a salt thereof,
(15) A compound as defined in term (14) wherein Ar1 and Ar2 are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula: 
X is a bond or an oxygen atom; Y is a group represented by the formula:
xe2x80x94(CH2)m1-Y3xe2x80x94(CH2)n1-Y4xe2x80x94
xe2x80x83wherein Y3 is a bond or xe2x80x94CH(OH)xe2x80x94, Y4 is an oxygen atom, S or NH, and m1 and n1 are independently an integer from 0 to 4 (sum of m1 and n1 is not more than 6); R1a is (1) a hydrogen atom, (2) a carboxyl group, (3) a C1-6 alkoxy-carbonyl group, (4) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C1-6 alkoxy-carbonyl and (iv) carbamoyl, or (5) a carbamoyl group which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl; and R2, R3 and R7 are a hydrogen atom,
(16) {circle around (1)} 6-[6-[4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazine,
{circle around (2)} 6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazine,
{circle around (3)} 3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine,
{circle around (4)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic acid, or a salt thereof,
(17) A compound represented by the formula: 
wherein the symbols have the same meanings as defined in term (1), or a salt thereof,
(18) A compound as defined in term (17) wherein the partial structural formula: 
(wherein the symbols have the same meanings as defined in term (1)) represents the formula: 
(wherein the symbols have the same meanings as defined in term (1)), provided that R1b is a hydrogen atom,
(19) A compound as defined in term (17) wherein Ar1 and Ar2 are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula: 
X is an oxygen atom; Y is a group represented by the formula:
xe2x80x94(CH2)w-Y5xe2x80x94
xe2x80x83wherein w is an integer from 1 to 6, and Y5 is an oxygen atom or NH; R1b is
(1) a hydrogen atom, or
(2) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C1-6 alkoxy-carbonyl, (iii) C1-6 alkyl-carbonyloxy and (iv) C1-6 alkyl-carbonyloxy-C1-6 alkoxy-carbonyl; and R2, R3 and R7 are a hydrogen atom,
(20) {circle around (1)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one,
{circle around (2)} ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate,
{circle around (3)} 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionic acid,
{circle around (4)} 4pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate,
{circle around (5)} pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate, or a salt thereof,
(21) A pro-drug of a compound as defined in term (1).
(22) A method for producing a compound as defined in term (1), which comprises reacting a compound represented by the formula: 
wherein Q1 represents a leaving group; the other symbols have the same meanings as defined in term (1), or a salt thereof, with a compound represented by the formula: 
wherein Q2 represents a leaving group; the other symbols have the same meanings as defined in term (1), or a salt thereof,
(23) A method for producing a compound as defined in term (14), which comprises reacting a compound represented by the formula: 
wherein Q1 represents a leaving group; the other symbols have the same meanings as defined in term (1), or a salt thereof, with a compound represented by the formula: 
wherein Q2 represents a leaving group; the other symbols have the same meanings as defined in term (1), or a salt thereof,
(24) A method for producing a compound as defined in term (17), which comprises reacting a compound represented by the formula: 
wherein Q1 represents a leaving group; the other symbols have the same meanings as-defined in term (1), or a salt thereof, with a compound represented by the formula: 
wherein Q2 represents a leaving group; the other symbols have the same meanings as defined in term (1), or a salt thereof,
(25) A pharmaceutical composition containing a compound as defined in term (1) or a pro-drug as defined in term (21),
(26) A pharmaceutical composition as defined in term (25) which is an anti-histaminic and/or eosinophil chemotaxis-inhibiting agent,
(27) A pharmaceutical composition as defined in term (25) which is an anti-allergic agent,
(28) A pharmaceutical composition as defined in term (25) which is an agent for preventing or treating asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopic dermatitis,
(29) A method for suppressing histamine and/or eosinophil chemotaxis comprising administering an effective amount of a compound as defined in term (1) or a pro-drug as defined in term (21) to mammals,
(30) A method for treating allergic diseases comprising administering an effective amount of a compound as defined in term (1) or a pro-drug as defined in term (21) to mammals,
(31) A method for treating asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopic dermatitis which comprises administering an effective amount of a compound as defined in term (1) or a pro-drug as defined in term (21) to mammals,
(32) Use of a compound as defined in term (1) or a pro-drug as defined in term (21) for producing an anti-histaminic and/or eosinophil chemotaxis-inhibiting agent,
(33) Use of a compound as defined in term (1) or a pro-drug as defined in term (21) for producing an anti-allergic agent, and
(34) Use of a compound as defined in term (1) or a pro-drug as defined in term (21) for producing an agent for preventing or treating asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopic dermatitis.
And, the present invention also provides:
(35) A compound as defined in term (1) wherein Ar1 and Ar2 are independently {circle around (1)} a C6-14 aromatic hydrocarbon group, or {circle around (2)} a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms, or {circle around (3)} a monovalent group resulting from removal of an optionally selected hydrogen atom from a condensed ring formed by said aromatic heterocyclic group and C6-14 aromatic hydrocarbon group, which C6-14 aromatic hydrocarbon group, 5- to 8-membered aromatic heterocyclic group and monovalent group may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo; and Ar1 and Ar2, along with the adjacent carbon atom, may form a condensed cyclic group represented by the formula: 
xe2x80x83wherein R7 is a hydrogen atom, a hydroxy group which may be substituted by C1-6 alkyl or a carboxyl group, which condensed cyclic group may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl (or carbamoyl), (xx) mono-C1-6 alkyl-carbamoyl (or mono-C1-6 alkyl-carbamoyl), (xxi) di-C1-6 alkyl-carbamoyl (or di-C1-6 alkyl-carbamoyl), (xxii) C6-10 aryl-carbamoyl (or C6-10 aryl-carbamoyl), (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo; the ring B is a 3- to 13-membered nitrogen-containing heterocycle which contains at least one nitrogen atom, and which may contain 1 to 3 hetero atoms selected from among a nitrogen atom, an oxygen atom and a sulfur atom, which 3- to 13-membered nitrogen-containing heterocycle may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo; X and Y, whether identical or not, are {circle around (1)} a bond, {circle around (2)} an oxygen atom, {circle around (3)} S(O)p wherein p is an integer from 0 to 2, {circle around (4)} NR4 wherein R4 is a hydrogen atom or a linear or branched C1-6 alkyl group or {circle around (5)} a divalent linear C1-6 hydrocarbon group which may contain 1 to 3 hetero atoms selected from among an oxygen atom and a sulfur atom, and which optionally have a substituent selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo; R1a is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy groups, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C16 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo; (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo,
(4) an acyl group represented by the formula xe2x80x94(Cxe2x95x90O)xe2x80x94R8, xe2x80x94SO2xe2x80x94R8, xe2x80x94SOxe2x80x94R8, xe2x80x94(Cxe2x95x90O)NR8R9, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R8, xe2x80x94(Cxe2x95x90S)Oxe2x80x94R8 or xe2x80x94(Cxe2x95x90S)NR8R9 wherein R8 is (a) a hydrogen atom, (b) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy groups, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 ararkyloxy and (xxviii) oxo, or (c) a group represented by the formula xe2x80x94OR10 wherein R10 is a hydrogen atom or a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy groups, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo, R9 is a hydrogen atom or a C1-6 alkyl group, or
(5) a group represented by the formula xe2x80x94OR1 wherein R1 is a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy groups, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, c(xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo;
xe2x80x83R1b, R2 and R3 are independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1-to 3 C1-6 alkoky groups, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo,
(4) an acyl group represented by the formula xe2x80x94(Cxe2x95x90O)xe2x80x94R12, xe2x80x94SO2xe2x80x94R12, xe2x80x94SOxe2x80x94R12, xe2x80x94(Cxe2x95x90O)NR12R13, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R12, xe2x80x94(Cxe2x95x90S)Oxe2x80x94R12 or xe2x80x94(Cxe2x95x90S)NR12R13 wherein R12 is (a) a hydrogen atom, (b) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy groups, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo, or (c) a group represented by the formula xe2x80x94OR14 wherein R14 is a hydrogen atom, or a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo, R13 is a hydrogen atom or a C1-6 alkyl group; or
(5) a group represented by the formula xe2x80x94OR15 wherein R15 is a hydrogen atom, or a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, a condensed group formed by a C3-6 cycloalkyl group and a benzene ring optionally having 1 to 3 C1-6 alkoxy, a C6-14 aryl group or a C7-16 aralkyl group, which may be substituted by a group selected from the group consisting of (i) a halogen atom, (ii) C1-6 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) optionally halogenated C2-6 alkynyl, (viii) C3-6 cycloalkyl, (ix) C1-6 alkoxy optionally having 1 to 3 halogen atoms, mono- or di-C1-6 alkylamino or C1-6 alkoxy-carbonyl, (x) optionally halogenated C1-6 alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C1-6 alkylamino, (xiv) di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C1-6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-6 alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C1-6 alkyl-carbamoyl or mono-C1-6 alkyl-thiocarbamoyl, (xxi) di-C1-6 alkyl-carbamoyl or di-C1-6 alkyl-thiocarbamoyl, (xxii) C6-10 aryl-carbamoyl or C6-10 aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C1-6 alkylsulfonyl, (xxv) C6-10 aryl, (xxvi) C6-10 aryloxy, (xxvii) C7-16 aralkyloxy and (xxviii) oxo;
xe2x80x83R7 is a hydrogen atom, a hydroxy group which may be substituted by C1-6 alkyl, or a carboxyl group.
Furthermore, when Compound (I) or a salt thereof has asymmetric carbon atoms in the structure thereof, optical isomers and racemates are included in the scope of the present invention. Compound (I) or a salt thereof may be a hydrate or anhydrate.
In Formula (I) above, ring A is a ring represented by the formula: 
wherein R1a is a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group having a substituent; R1b is a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group having a substituent.
With respect to Formula (I) above, Compound (I) wherein Ring A is Type (a) and Compound (I) wherein Ring A is Type (b) are hereinafter referred to as Compound (Ia) and Compound (Ib), respectively. 
In Formula (I) above, Ar1 and Ar2 are an xe2x80x9caromatic group optionally having a substituent,xe2x80x9d and may form a condensed ring group with an adjacent carbon atom.
Examples of the xe2x80x9caromatic groupxe2x80x9d represented by Ar1 and Ar2 include {circle around (1)} monocyclic or condensed polycyclic aromatic hydrocarbon groups, specifically 6- to 14-membered monocylic or condensed polycyclic aromatic hydrocarbon groups such as C6-14 aryl groups (e.g., phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.) (preferably phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, etc., particularly preferably phenyl, etc.), or {circle around (2)} monocyclic groups (preferably 5- to 8-membered) containing 1 or more (e.g., 1 to 4, preferably 1 to 3) of one or two kinds of hetero atoms selected from among a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms, or condensed aromatic heterocyclic groups thereof, specifically aromatic heterocycles such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, thianthrene, furan, indolizine, xanthrene, phenoxathin, pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and isochroman (preferably pyridine, thiophene, furan, etc., more preferably pyridine etc.), or monovalent groups resulting from removal of an optionally selected hydrogen atom from a condensed ring formed by one of these rings (preferably monocyclic heterocycles mentioned above) and one or more than one (preferably 1 or 2, more preferably 1) aromatic ring (e.g., aromatic hydrocarbon groups mentioned above, preferably benzene ring, etc.).
The xe2x80x9caromatic groupxe2x80x9d of the xe2x80x9caromatic group optionally having a substituentxe2x80x9d represented by Ar1 and Ar2 is preferably phenyl or the like.
Examples of the xe2x80x9csubstituentxe2x80x9d for the aromatic group represented by Ar1 and Ar2 include: (i) halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (ii) lower alkylenedioxy groups (e.g., C1-3 alkylenedioxy groups such as methylenedioxy and ethylenedioxy), (iii) nitro groups, (iv) cyano groups, (v) optionally halogenated lower alkyl groups, (vi) optionally halogenated lower alkenyl groups, (vii) optionally halogenated lower alkynyl groups, (viii) lower cycloalkyl groups (e.g., C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (ix) lower alkoxy groups which may be substituted, (x) optionally halogenated lower alkylthio groups, (xi) hydroxy groups, (xii) amino groups, (xiii) mono-lower alkylamino groups (e.g., mono-C1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino and butylamino), (xiv) di-lower alkylamino groups (e.g., di-C1-6 alkylamino groups such as dimethylamino, diethylamino, dipropylamino and dibutylamino), (xv) 5- or 6-membered cyclic amino groups (e.g., morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl), (xvi) lower alkyl-carbonyl groups (e.g., C1-6 alkylcarbonyl groups such as acetyl and propionyl), (xvii) carboxyl groups, (xviii) lower alkoxy-carbonyl groups (e.g., C1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl), (xix) carbamoyl groups or thiocarbamoyl groups, (xx) mono-lower alkyl-carbamoyl groups (e.g., mono-C1-6 alkyl-carbamoyl groups such as methylcarbamoyl and ethylcarbamoyl) or mono-lower alkyl-thiocarbamoyl groups (e.g., mono-C1-6 alkyl-thiocarbamoyl groups such as methylthiocarbamoyl and ethylthiocarbamoyl), (xxi) di-lower alkyl-carbamoyl groups (e.g., di-C1-6 alkylcarbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl) or di-lower alkyl-thiocarbamoyl groups (e.g., di-C1-6 alkylthiocarbamoyl groups such as dimethylthiocarbamoyl and diethylthiocarbamoyl), (xxii) aryl-carbamoyl (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl) or aryl-thiocarbamoyl (e.g., C6-10 aryl-thiocarbamoyl such as phenylthiocarbamoyl and naphthylthiocarbamoyl), (xxiii) sulfo groups, (xxiv) lower alkylsulfonyl groups (e.g., C1-6 alkylsulfonyl groups such as methylsulfonyl and ethylsulfonyl), (xxv) aryl groups (e.g., C6-10 aryl groups such as phenyl and naphthyl), (xxvi) aryloxy groups (e.g., C6-10 aryloxy groups such as phenyloxy and naphthyloxy), (xxvii) aralkyloxy groups (e.g., C7-16 aralkyloxy groups such as benzyloxy), and (xxviii) oxo groups.
Examples of the xe2x80x9coptionally halogenated lower alkyl groupxe2x80x9d include lower alkyl groups (e.g., C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), specifically methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.
Examples of the xe2x80x9coptionally halogenated lower alkenyl groupxe2x80x9d and xe2x80x9coptionally halogenated lower alkynyl groupxe2x80x9d include lower alkenyl groups (e.g., C2-6 alkenyl groups such as vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl and 5-hexen-1-yl) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and lower alkynyl groups (e.g., C2-6 alkynyl groups such as 2-butyn-1-yl, 4-pentyn-1-yl and 5-hexyn-1-yl) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
Examples of the xe2x80x9clower alkoxy groups which may be substitutedxe2x80x9d include lower alkoxy groups (e.g., C1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), mono- or di-lower alkylamino groups (e.g., mono- or di-C1-6 alkylamino groups such as methylamino, dimethylamino, ethylamino and dimethylamino) or lower alkoxy-carbonyl groups (e.g., C1-6 alkoxy-carbonyl groups such as methoxycarbonyl and ethoxycarbonyl).
Examples of the xe2x80x9coptionally halogenated lower alkylthio groupxe2x80x9d include lower alkylthio groups (e.g., C1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), specifically methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
Specific examples of the condensed ring formed by Ar1 and Ar2, along with the adjacent carbon atom, include condensed ring groups represented by the formula: 
wherein R7 has the same definition as that shown above.
It is preferable that Ar1 and Ar2, whether identical or not, are an aromatic hydrocarbon group (e.g., C6-14 aromatic hydrocarbon group) optionally having a substituent, and a benzene ring optionally having a substituent is more preferred. More preferably, Ar1 and Ar2 are independently (1) phenyl group which may be substituted by a halogen atom or C1-6 alkyl, or (2) a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from among a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms.
In Formula (I) above, Ring B represents a xe2x80x9cnitrogen-containing heterocycle optionally having a substituent,xe2x80x9d provided that Ring B is not a heterocycle represented by the formula: 
wherein r is 0 or 1.
Examples of the xe2x80x9cnitrogen-containing heterocyclexe2x80x9d represented by Ring B include 3- to 13-membered nitrogen-containing heterocycles which contains one nitrogen atom, which may further contain 1 to 3 hetero atoms selected from among a nitrogen atom, an oxygen atom, a sulfur atom, etc. In Formula (I) above, it is preferable that Ring B form a divalent group resulting from removal of one hydrogen atom from the nitrogen atom and other atoms of Ring B, respectively. Specific examples include 3- to 9-membered (more preferably 3- to 6-membered) nitrogen atom-containing heterocyclic groups such as 
Examples of the substituent for the nitrogen-containing heterocycle represented by Ring B include the same as the substituent for the xe2x80x9caromatic group optionally having a substituentxe2x80x9d represented by Ar1 and Ar2 above.
Specific preferable examples of Ring B include a ring represented by the formula: 
wherein Z is a nitrogen atom or a methine group, Z1 and Z2 are independently a linear C1-4 alkylene group which may be substituted by a hydroxy group, an oxo group or a C1-6 alkyl group.
Examples of said xe2x80x9cC1-6 alkyl groupxe2x80x9d include linear or branched C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
Examples of said xe2x80x9clinear C1-4 alkylene groupxe2x80x9d include linear C1-4 alkylene groups such as methylene, ethylene, propylene and butylene.
Preferable examples of the xe2x80x9clinear C1-4 alkylene group which may be substituted by a hydroxy group, an oxo group or a C1-6 alkyl groupxe2x80x9d represented by Z1 and Z2 include unsubstituted linear C1-4 alkylene groups, and unsubstituted linear C1-2 alkylene groups are more preferred.
Ring B is more preferably piperidine, piperazine, or the like.
In Formula (I) above, X and Y, whether identical or not, are {circle around (1)} a bond, {circle around (2)} an oxygen atom, {circle around (3)} S(O)p (p is an integer from 0 to 2), {circle around (4)} NR4 wherein R4 is a hydrogen atom or a lower alkyl group, or {circle around (5)} a divalent linear lower hydrocarbon group which may contain a substituent, and which may further contain 1 to 3 hetero atoms.
Examples of the lower alkyl group represented by R4 include linear or branched C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
Examples of the xe2x80x9cdivalent linear lower hydrocarbon group which may further contain 1 to 3 hetero atomsxe2x80x9d represented by X and Y include groups resulting from removal of each of hydrogen atoms (2 in total) bound to the same or different carbon atom from a lower (C1-6) hydrocarbon, and which may optionally contain hetero atoms selected from among an oxygen atom, a sulfur atom, etc., in the hydrocarbon chain.
Specific examples of the xe2x80x9cdivalent linear lower hydrocarbon groupxe2x80x9d include
(i) C1-6 alkylene groups (e.g., xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, etc.),
(ii) C2-6 alkenylene groups (e.g., xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, etc.), and
(iii) C2-6 alkynylene groups (e.g., xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)2xe2x80x94, (CH2)3xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, etc.).
Examples of the xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cdivalent linear lower hydrocarbon group which may further contain 1 to 3 hetero atoms,xe2x80x9d represented by X and Y include the same as the xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic group optionally having a substituentxe2x80x9d represented by Ar1 and Ar2 above, and is preferably a hydroxy group or an oxo group.
X is preferably a bond, an oxygen atom or NH, and a bond or an oxygen atom is particularly preferred.
Preferable examples of Y include a group represented by the formula:
xe2x80x94(CH2)m-Y1xe2x80x94(CH2)n-Y2xe2x80x94
wherein Y1 and Y2 whether identical or not, are a bond, an oxygen atom, S(O)p wherein p has the same definition as that shown above, NR4 wherein R4 has the same definition as that shown above, a carbonyl group, a carbonyloxy group or a group represented by the formula: 
wherein R5 and R6, whether identical or not, are a hydroxy group or a C1-4 alkyl group; m and n are independently an integer from 0 to 4 (sum of m and n is not more than 6).
Examples of the xe2x80x9cC1-4 alkyl groupxe2x80x9d represented by R5 and R6 include linear or branched C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
Preferable examples of Y include
(i) C1-6 alkylene groups, (ii) xe2x80x94(CH2)p1Oxe2x80x94,
(iii) xe2x80x94(CH2)p1NHxe2x80x94,
(iv) xe2x80x94(CH2)p1Sxe2x80x94,
(v) xe2x80x94(CH2)q1CH(OH)(CH2)q2Oxe2x80x94,
(vi) xe2x80x94(CH2)q1CH(OH)(CH2)q2NHxe2x80x94,
(vii) xe2x80x94(CH2)q1CH(OH)(CH2)q2Sxe2x80x94,
(viii) xe2x80x94(CH2)p1CONHxe2x80x94,
(ix) xe2x80x94COO(CH2)p1Oxe2x80x94,
(x) xe2x80x94COO(CH2)p1NHxe2x80x94,
(xi) xe2x80x94COO(CH2)p1Sxe2x80x94,
(xii) xe2x80x94(CH2)q1O(CH2)q2Oxe2x80x94,
(xiii) xe2x80x94(CH2)q1O(CH2)q2NHxe2x80x94 or
(xiv) xe2x80x94(CH2)q1O(CH2)q2Sxe2x80x94 wherein p1 is an integer from 1 to 6, q1 and q2 are an integer from 1 to 3.
In particular, Y is preferably a bond, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94, xe2x80x94(CH2)6xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94, xe2x80x94(CH2)3xe2x80x94NHxe2x80x94, xe2x80x94(CH2)4xe2x80x94NHxe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94(CH2)6xe2x80x94NHxe2x80x94, xe2x80x94(CH2)6xe2x80x94Sxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Sxe2x80x94, or the like.
In the case of Compound (Ia), Y is preferably a group represented by the formula:
xe2x80x94(CH2)m-Y3xe2x80x94(CH2)n-Y4xe2x80x94
wherein Y3 is a bond or xe2x80x94CH(OH)xe2x80x94, Y4 is an oxygen atom, S or NH, and m and n independently are an integer from 0 to 4 (sum of m and n is not more than 6). In particular, m and n are preferably an integer from 1 to 3, and 3 is more preferred. When Y3 is xe2x80x94CH(OH)xe2x80x94, m and n are preferably 1.
In the case of Compound (Ib), Y is preferably a group represented by the formula:
xe2x80x94(CH2)w-Y5xe2x80x94
wherein w is an integer from 1 to 6, and Y5 is an oxygen atom or NH. In particular, w is preferably an integer from 1 to 3, and 3 is more preferred.
In Formula (I) above, R1a, whether identical or not, is a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group having a substituent.
R1b, whether identical or not, is a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group having a substituent.
R2 and R3, whether identical or not, are a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an acyl group or a hydroxy group having a substituent.
Examples of the xe2x80x9chalogen atomxe2x80x9d represented by R1a, R1b, R2 and R1 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples of the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group optionally having a substituentxe2x80x9d represented by R1a, R1b, R2 and R3 include groups resulting from removal of one hydrogen atom from a hydrocarbon compound, specifically linear or cyclic hydrocarbon groups such as alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups and aralkyl groups. In particular, chain (linear or branched) or cyclic hydrocarbon groups, etc. having 1 to 16 carbon atoms are preferred, with greater preference given to
(a) alkyl groups, preferably lower alkyl groups (e.g., C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl),
(b) alkenyl groups, preferably lower alkenyl groups (e.g., C2-6 alkenyl groups such as vinyl, allyl, isopropenyl, butenyl, isobutenyl and sec-butenyl),
(c) alkynyl groups, preferably lower alkynyl groups (e.g., C2-6 alkynyl groups such as propargyl, ethynyl, butynyl and 1-hexynyl),
(d) cycloalkyl groups, preferably lower cycloalkyl groups (e.g., C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl which may condense with a benzene ring optionally having 1 to 3 lower alkoxy groups (e.g., C1-6 alkoxy groups such as methoxy),
(e) aryl groups (e.g., C6-14 aryl groups such as phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, preferably phenyl groups), and
(f) aralkyl groups (preferably lower aralkyl groups (e.g., C7-16 aralkyl groups such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentyl, more preferably benzyl groups).
Examples of the xe2x80x9csubstituentxe2x80x9d for said xe2x80x9chydrocarbon groupxe2x80x9d include the same as the xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic group optionally having a substituentxe2x80x9d represented by Ar1 and Ar2 above.
In particular, examples of preferred hydrocarbons include alkyl groups such as C1-6 alkyl groups, and examples of substituents for hydrocarbon groups include cyano, carboxyl, C1-6 alkoxy-carbonyl and carbamoyl (or thiocarbamoyl).
Examples of the xe2x80x9cacyl groupxe2x80x9d represented by R1a, R1b, R2 and R3 include groups represented by the formula xe2x80x94(Cxe2x95x90O)xe2x80x94R8, xe2x80x94SO2xe2x80x94R8, xe2x80x94SOxe2x80x94R8, xe2x80x94(Cxe2x95x90O)NR8R9, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R8, xe2x80x94(Cxe2x95x90S)Oxe2x80x94R8 or xe2x80x94(Cxe2x95x90S)NR8R9 wherein R8 is a hydrogen atom, a hydrocarbon group optionally having a substituent or a hydroxy group optionally having a substituent; and R9 is a hydrogen atom or a lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl, preferably a C1-3 alkyl group such as methyl, ethyl, propyl or isopropyl).
In particular, groups represented by the formula xe2x80x94(Cxe2x95x90O)xe2x80x94R8, xe2x80x94SO2xe2x80x94R8xe2x80x94, xe2x80x94SOxe2x80x94R8, xe2x80x94(Cxe2x95x90O)NR8R9 or xe2x80x94(Cxe2x95x90O)Oxe2x80x94R8 are preferred, and groups represented by the formula xe2x80x94(Cxe2x95x90O)xe2x80x94R8 are more preferred.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d represented by R8 is the same as the xe2x80x9chydrocarbon group optionally having a substituentxe2x80x9d represented by R1a, R1b, R2 and R3 above. In particular, the hydrocarbon group represented by R8 is preferably an alkyl group such as a C1-6 alkyl group, and the substituent thereof is preferably carboxyl, C1-6 alkoxy-carbonyl, or the like. R9 is preferably a hydrogen atom or the like.
Examples of the xe2x80x9chydroxy group optionally having a substituentxe2x80x9d represented by R1a include hydroxy groups having one group such as a hydrocarbon group optionally having a substituent, instead of a hydrogen atom of the hydroxy group.
Examples of the xe2x80x9chydroxy group optionally having a substituentxe2x80x9d represented by R1b, R2, R3 and R8 include (1) a hydroxy group or (2) a hydroxy group having one group such as a hydrocarbon group optionally having a substituent, instead of a hydrogen atom of the hydroxy group.
The xe2x80x9chydrocarbon group optionally having a substituentxe2x80x9d present in the hydroxy group is the same as the xe2x80x9chydrocarbon group optionally having a substituentxe2x80x9d represented by R1a, R1b, R2, R3 and R8 above.
With respect to Compound (Ia), the acyl group represented by R1a, R1b, R2 and R3 above is preferably {circle around (1)} a carboxyl group, {circle around (2)} a C1-6 alkoxy-carbonyl group, {circle around (3)} a carbamoyl group (or thiocarbamoyl group) which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl, or the like.
In particular, R1a is preferably (1) a hydrogen atom, (2) a carboxyl group, (3) a C1-6 alkoxy-carbonyl group, (4) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C1-6 alkoxy-carbonyl and (iv) carbamoyl (or thiocarbamoyl) or (5) a carbamoyl group (or thiocarbamoyl group) which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl, or the like.
With respect to Compound (Ib), when R1b is a hydrogen atom, the oxo group of the triazolo[4,3-b]pyridazine ring may be enolated, and the partial structural formula: 
may represent any of the formula: 
In particular, R1b is preferably
(1) a hydrogen atom,
(2) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C1-6 alkoxy-carbonyl, (iii) C1-6 alkyl-carbonyloxy and (iv) C1-6 alkyl-carbonyloxy-C1-6 alkoxy-carbonyl, or the like.
With respect to Formula (I) above, R2 and R3 are preferably a hydrogen atom.
In Formula (I) above, R7 represents a hydrogen atom, a hydroxy group which may be substituted by a lower alkyl group or a carboxyl group.
Examples of the xe2x80x9clower alkyl groupxe2x80x9d of the xe2x80x9chydroxy group which may be substituted by a lower alkyl groupxe2x80x9d include C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
R7 is preferably a hydrogen atom or a hydroxy group, and a hydrogen atom is particularly preferred.
As Compound (I) of the present invention, the following are preferred:
Compound (I) wherein R1a is
(1) a hydrogen atom,
(2) a carboxyl group,
(3) a C1-6 alkoxy-carbonyl group,
(4) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C1-6 alkoxy-carbonyl and (iv) carbamoyl, or
(5) a carbamoyl group which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl;
R1b is
(1) a hydrogen atom, or
(2) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C1-6 alkoxy-carbonyl, (iii) C1-6 alkyl-carbonyloxy and (iv) C1-6 alkyl-carbonyloxy-C1-6 alkoxy-carbonyl;
R2 and R3 are a hydrogen atom;
R7 is a hydrogen atom or a hydroxy group (particularly a hydrogen atom);
Ar1 and Ar2 are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula: 
X is a bond or an oxygen atom;
Y is a group represented by the formula:
xe2x80x94(CH2)m-Y3xe2x80x94(CH2)n-Y4xe2x80x94
xe2x80x83wherein Y3 is a bond or xe2x80x94CH(OH)xe2x80x94, Y4 is an oxygen atom, S or NH, and m and n are independently an integer from 0 to 6 (sum of m and n is not more than 6).
{circle around (1)} 6-[6-[4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazine or a salt thereof.
{circle around (2)} 6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazine or a salt thereof.
{circle around (3)} 3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino)propoxy][1,2,4]triazolo[4,3-b]pyridazine or a salt thereof.
{circle around (4)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic acid or a salt thereof.
{circle around (5)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one or a salt thereof.
{circle around (6)} Ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate or a salt thereof.
{circle around (7)} 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionic acid or a salt thereof.
{circle around (8)} Pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate or a salt thereof.
{circle around (9)} Pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate or a salt thereof.
As Compound (Ia) of the present invention, the following are preferred:
Compound (Ia) wherein Ar1 and Ar2 are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula: 
X is a bond or an oxygen atom;
Y is a group represented by the formula:
xe2x80x94(CH2)m-Y3xe2x80x94(CH2)n-Y4xe2x80x94
xe2x80x83wherein Y3 is a bond or xe2x80x94CH(OH)xe2x80x94, Y4 is an oxygen atom, S or NH, and m and n are independently an integer from 0 to 4 (sum of m and n is not more than 6);
R1a is
(1) a hydrogen atom,
(2) a carboxyl group,
(3) a C1-6 alkoxy-carbonyl group,
(4) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C1-6 alkoxy-carbonyl and (iv) carbamoyl (or thiocarbamoyl), or
(5) a carbamoyl group (or thiocarbamoyl group) which may be substituted by a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl; and R2, R3 and R7 are a hydrogen atom.
{circle around (1)} 6-[6-(4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazine or a salt thereof.
{circle around (2)} 6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazine or a salt thereof.
{circle around (3)} 3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine or a salt thereof.
{circle around (4)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic acid or a salt thereof.
As Compound (Ib) of the present invention, the following are preferred:
Compound (Ib) wherein Ar1 and Ar2 are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula: 
X is an oxygen atom; Y is a group represented by the formula:
xe2x80x94(CH2)w-Y5xe2x80x94
wherein w is an integer from 1 to 6, and Y5 is an oxygen atom or NH; R1b is (1) a hydrogen atom, or (2) a C1-6 alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C1-6 alkoxy-carbonyl, (iii) C1-6 alkyl-carbonyloxy and (iv) C1-6 alkyl-carbonyloxy-C1-6 alkoxy-carbonyl; and R2, R3 and R7 are a hydrogen atom.
{circle around (1)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one or a salt thereof.
{circle around (2)} Ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino)propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate or a salt thereof.
{circle around (3)} 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionic acid or a salt thereof.
{circle around (4)} Pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate or a salt thereof.
{circle around (5)} Pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)-2-methylpropionate or a salt thereof.
The pro-drug of Compound (I) of the present invention may be a compound which is converted into Compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in the living body, i.e., a compound which is converted into Compound (I) upon enzymatic oxidation, reduction, hydrolysis, or the like, or a compound which is converted into Compound (I) upon hydrolysis or the like with gastric acid or the like.
Examples of the pro-drug of Compound (I) include compounds wherein the amino group of Compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds wherein the amino group of Compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, or the like); compounds wherein the hydroxy group of Compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds wherein the hydroxy group of Compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, or the like); and compounds wherein the carboxyl group of Compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, cyclohexyloxycarbonylethyl-esterified, methyl-amidated, or the like. These compounds can be produced by per se known methods from Compound (I).
In addition, the pro-drug of Compound (I) of the present invention may be a compound which is converted into Compound (I) under physiological conditions as described in xe2x80x9cPharmaceutical Research and Development,xe2x80x9d Vol. 7 (Drug Design), pages 163-198, published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).
Methods for producing Compound (I) of the present invention or a salt thereof are described below.
(A) Of Compound (I) of the present invention or a salt thereof, Compound (Ia) or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein Q1 represents a leaving group; the other symbols have the same definitions as those shown above, or a salt thereof, with a compound represented by the formula: 
wherein Q2 represents a leaving group; the other symbols have the same definitions as those shown above, or a salt thereof.
Examples of the leaving group represented by Q1 include alkali metals such as sodium and potassium. Q1 may be a hydrogen atom.
Examples of the leaving group represented by Q2 induce halogen atoms (e.g., chlorine atom, bromine atom, iodine atom), C6-10 arylsulfonyloxy groups (e.g., benzenesulfonyloxy, p-tolylsulfonyloxy) and C1-4 alkyl-sulfonyloxy groups (e.g., methanesulfonyloxy).
In this reaction, Compound (IIa) or a salt thereof is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (IlIa) or a salt thereof. This condensation reaction is preferably carried out in the presence of a base.
Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate.
In addition, this reaction can also be carried out in an inert solvent exemplified by alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
(B) Also, Compound (Ia) of the present invention or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof, with a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof.
In this reaction, Compound (IVa) or a salt thereof is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (Va) or a salt thereof. This condensation reaction is preferably carried out in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate.
In addition, this reaction can also be carried out in an inert solvent exemplified by alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrbfuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
(C) Compound (Ia) of the present invention or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof, with a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof.
In this reaction, Compound (VIa) or a salt thereof is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (VIIa) or a salt thereof.
In addition, this reaction can also be carried out in an inert solvent exemplified by alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
(D) Also, Compound (Ia) of the present invention or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein R1axe2x80x2 is a cyano group, an alkoxycarbonyl group, a carboxyl group, a substituted carbamoyl group, or a C1-6 alkyl group which may be substituted by cyano, alkoxycarbonyl, carboxyl, substituted carbamoyl, or the like; the other symbols have the same definitions as those shown above, or a salt thereof, with an acid or a base.
Examples of the alkoxycarbonyl group represented by R1a include C1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl.
Examples of the substituted carbamoyl group represented by R1axe2x80x2 include mono-lower alkyl-carbamoyl groups (e.g., mono-C1-6 alkyl-carbamoyl groups such as methylcarbamoyl and ethylcarbamoyl), di-lower alkyl-carbamoyl groups (e.g., di-C1-6 alkylcarbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl), and aryl-carbamoyl groups (e.g., C6-10 aryl-carbamoyl groups such as phenylcarbamoyl and naphthylcarbamoyl).
Examples of the C1-6 alkyl group represented by R1axe2x80x2 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. The alkoxycarbonyl and substituted carbamoyl which is a substituent for this C1-6 alkyl group is the same as the alkoxycarbonyl and substituted carbamoyl represented by R1axe2x80x2.
In this reaction, an acid or a base is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (Iaxe2x80x2) or a salt thereof.
Examples of the base used for this reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate.
Examples of the acid used for this reaction include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid.
In addition, this reaction can also be carried out in a solvent exemplified by water; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
Compound (Ia) thus obtained can be converted into a salt by a conventional method. When Compound (Ia) is obtained as a salt, it can be converted into a free form or another salt by a conventional method. Compound (Ia) or a salt thereof thus obtained can be isolated and purified by known means such as solvent extraction, liquid-liquid transformation, re-dissolution, salting-out, crystallization, recrystallization and chromatography. When Compound (Ia) or a salt thereof contains optical isomers, it can be resolved into the R- and S-configurations by an ordinary means of optical resolution.
Methods for producing Starting Compounds (IIa) through (VIIIa) or salts thereof which are used to produce Compound (Ia) of the present invention or a salt thereof are described below.
Salts of these Compounds (Ia) through (VIIIa) include, for example, salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid,fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid). Provided that these compounds have an acidic group such as that of a carboxylic acid, as a substituent, the acidic group may form a salt with an inorganic base (e.g., alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium, or ammonia) or an organic base (e.g., tri-C1-3 alkylamine such as triethylamine).
Starting Compounds (IIa) and (IVa) or salts thereof can, for example, be synthesized by the method described in the Journal of Medicinal Chemistry, Vol. 32, p. 583 (1989), or a modification thereof.
Starting Compound (IIIa) or a salt thereof can, for example, be synthesized by the method described in the Journal of the Pharmaceutical Society of Japan, Vol. 75, p. 1242 (1955), or a modification thereof.
Starting Compounds (Va) and (VIIa) or salts thereof can, for example, be synthesized by the methods described in Japanese Patent Unexamined Publication No. 223287/1991 etc., or modifications thereof.
Starting Compounds (VIa) or a salt thereof can, for example, be synthesized by the method described in the Journal of Medicinal Chemistry, Vol. 38, p. 2472 (1995), or a modification thereof.
Although these starting compound or salts thereof thus obtained can be isolated and purified by known means such as solvent extraction, liquid-liquid transformation, re-dissolution, salting-out, crystallization, recrystallization and chromatography, they may also be used as a starting material for the next process in the form of a reaction mixture as-is without isolation.
(A) On the other hand, Compound (Ib) of the present invention or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof, with a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof.
In this reaction, Compound (IIb) or a salt thereof is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (IIIb) or a salt thereof. This condensation reaction is preferably carried out in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide.; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate.
In addition, this reaction can also be carried out in a solvent exemplified by alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
(B) Also, Compound (Ib) of the present invention or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein the symbols have the same definitions as those shown above, or a salt thereof, with a compound represented by the formula:
Q2xe2x80x94R1bxe2x80x83xe2x80x83(Vb)
wherein the symbols have the same definitions as those shown above, or a salt thereof.
In this reaction, Compound (Vb) or a salt, thereof is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (IVb) or a salt thereof. This condensation reaction is preferably carried out in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate.
In addition, this reaction can also be carried out in an inert solvent exemplified by alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
(C) Also, Compound (Ib) of the present invention or a salt thereof can be produced by reacting a compound represented by the formula: 
wherein R1bxe2x80x2 is a cyano group, an alkoxycarbonyl group, a carboxyl group, a substituted carbambyl group, or a C1-6 alkyl group which may be substituted by cyano, alkoxycarbonyl, carboxyl, substituted carbamoyl, or the like; the other symbols have the same definitions as those shown above, or a salt thereof, with an acid or a base. Each group represented by R1bxe2x80x2 has the same definition as that represented by R1axe2x80x2.
In this reaction, an acid or a base is normally used at 1 to 5 mol, preferably 1 to 2 mol, per mol of Compound (Ibxe2x80x2) or a salt thereof.
Examples of the base used for this reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate.
Examples of the acid used for this reaction include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid.
In addition, this reaction can also be carried out in an inert solvent exemplified by water; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.
Reaction temperature is normally 10 to 200xc2x0 C., preferably 50 to 100xc2x0 C.
Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6 hours.
Compound (Ib) thus obtained can be converted into a salt by a conventional method. When Compound (Ib) is obtained as a salt, it can be converted into a free form or another salt by a conventional method. Compound (Ib) or a salt thereof thus obtained can be isolated and purified by known means such as solvent extraction, liquid-liquid transformation, re-dissolution, salting-out, crystallization, recrystallization and chromatography. When Compound (Ib) or a salt thereof contains optical isomers, they can be resolved into the R- and S-configurations by an ordinary means of optical resolution.
Methods for producing Starting Compounds (IIb) and (IIIb) or salts thereof which are used to produce Compound (Ib) of the present invention or a salt thereof are described below.
Salts of these Compounds (Ib) through (IIIb) include, for example, salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid). Provided that these compounds have an acidic group such as that of a carboxylic acid, as a substituent, the acidic group may form a salt with an inorganic base (e.g., alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium, or ammonia) or an organic base (e.g., tri-C1-3 alkylamine such as triethylamine).
Starting Compound (IIb) or a salt thereof can, for example, be synthesized by the method described in the Journal of Medicinal Chemistry, Vol. 32, p. 583 (1989), or a modification thereof.
Starting Compound (IIIb) or a salt thereof can, for example, be synthesized by the method described in the Journal of Heterocyclic Chemistry, Vol. 13, p. 673 (1976), or a modification thereof.
Although these starting compound or salts thereof thus obtained can be isolated and purified by known means such as solvent extraction, liquid-liquid transformation, re-dissolution, salting-out, crystallization, recrystallization and chromatography, they may also be used as a starting material for the next process in the form of a reaction mixture as-is without isolation.
Also, when the starting compound used in each of the above-mentioned reactions for producing Compounds (Ia) and (Ib) of the present invention or salts thereof or for synthesizing starting compounds has an amino group, a carboxyl group or a hydroxyl group as a substituent, these substituents may have a protective group in common use in peptide chemistry etc. incorporated therein; the desired compound can be obtained by removing, as appropriate, the protective group after completion of the reaction.
Amino group-protecting groups include, for example, formyl, C1-6 alkylcarbonyls optionally having a substituent (e.g., acetyl, ethylcarbonyl), phenylcarbonyl, C1-6 alkyl-oxycarbonyls (e.g., methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl, C7-10 aralkyl-carbonyls (e.g., benzylcarbonyl), trityl, phthaloyl and N,N-dimethylaminomethylene. Substituents for these groups include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C1-6 alkyl-carbonyls (e.g., mrethylcarbonyl, ethylcarbonyl, butylcarbonyl) and nitro groups, the number of substituents being about 1 to 3.
Carboxyl group-protecting groups include, for example, C1-6 alkyls optionally having a substituent (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl), phenyl, trityl and silyl. Substituents for these groups include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, C1-6 alkyl-carbonyls (e.g., acetyl, ethylcarbonyl, butylcarbonyl) and nitro groups, the number of substituents being about 1 to 3.
Hydroxy group-protecting groups include, for example, C1-6 alkyls optionally having a substituent (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl), phenyl, C7-10 aralkyls (e.g., benzyl), formyl, C1-6 alkyl-carbonyls (e.g., acetyl, ethylcarbonyl), phenyloxycarbonyl, benzoyl, C7-10 aralkyl-carbonyls (e.g., benzylcarbonyl), pyranyl, furanyl and silyl. Substituents for these groups include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C1-6 alkyls (e.g., methyl, ethyl, n-propyl), phenyl, C7-10 aralkyls (e.g., benzyl) and nitro groups, the number of substituents being about 1 to 4.
The protecting groups can be removed by commonly known methods or modifications thereof, including treatments with acids, bases, reducing agents, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
The compound (I) of the present invention or a salt thereof (including a pro-drug of the compound (I)) can be safely used as an anti-allergic agent in mammals (e.g., humans, mice, dogs, rats, bovines), because it exhibits excellent anti-allergic, anti-histaminic, anti-inflammatory, anti-PAF (platelet-activating factor) or eosinophil chemotaxis-inhibiting activity, etc., with low toxicity (acute toxicity: LD50 greater than 2 g/kg).
Furthermore, the compound (I) of the present invention or a salt thereof exhibits an eosinophil chemotaxis-inhibiting activity as well as an anti-histaminic activity, and can be used to treat or prevent allergic diseases such as chronic urticaria and other forms of urticaria (e.g., acute urticaria), atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and hypersensitivity pneumonitis; dermal diseases (especially allergic dermal diseases) such as itching, herpetic dermatitis, eczematous dermatitis, contact dermatitis, prurigo, and psoriasis; respiratory diseases such as eosinophilic pneumonia (PIE syndrome), chronic obstructive pulmonary disease (COPD), and asthma; increased nasal cavity resistance, sneezing, nasal discharge, pollenosis, upper airway hypersensitivity, etc., in the mammals mentioned above. In particular, Compound (I) or a salt thereof is used as a preventive or therapeutic agent for asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, or the like. The route of administration may be oral or non-oral.
Also, the preparation for the present invention may contain as active ingredients pharmaceutical components other than the compound (I) or a salt therof. Such pharmaceutically active components include, for example, anti-asthmatics (e.g., theiphylline, procaterol, ketotifen, azelastine, seratrodast), anti-allergic agents (g.g., ketotifen, terfenadine, azelastine, epinastine), anti-inflammatory agents (e.g., cefixime, cefdinir, ofloxacin, tosufloxacin) and antifungal agents (e.g., fluconazole, itraconazole). These components are not subject to limitation, as long as the object of the present invention is accomplished, and may be used in appropriate mixing ratios. Useful dosage forms include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, suspensions, injectable preparations, inhalants, ointments, eyedrops, aerosols, eye ointments, plasters, suppositories, troches, poultices, and liniments, these preparations are prepared by conventional methods (e.g., methods described in the Japanese Pharmacopoeia).
In the preparation of the present invention, the content of the compound (I) or a salt thereof is normally about 0.01 to 100% by weight, preferably 0.1 to 50% by weight, and more preferably 0.5 to 20% by weight, relative to the entire preparation, depending on the form of the preparation.
Specifically, tablets can be produced by granulating a pharmaceutical as-is, or in a uniform mixture with an excipient, a binder, a disintegrating agent or other appropriate additives, by an appropriate method, then adding lubricants etc., and subjecting the mixture to compressive shaping, or by subjecting to direct compressive shaping a pharmaceutical as-is, or in a uniform mixture with an excipient, a binder, a disintegrating agent or other appropriate additives, or subjecting to compressive shaping previously prepared granules as-is, or in a uniform mixture with appropriate additives. These tablets may incorporate coloring agents, correctives etc. as necessary, and may be coated with appropriate coating agents.
Injectable preparations can be produced by dissolving, suspending or emulsifying a given amount of a pharmaceutical in an aqueous solvent such as water for injection, physiological saline or Ringer""s solution, or a non-aqueous solvent such as a vegetable oil, and diluting to a given amount, or transferring a given amount of a pharmaceutical into a container for injection and sealing the container.
Examples of the carriers for oral preparations include substances in common use in pharmaceutical production, such as starch, mannitol, crystalline cellulose and carboxymethyl cellulose sodium. Examples of the carriers for injectable preparations include distilled water, physiological saline, glucose solutions and transfusions. Other additives in common use for pharmaceutical production can also be added, as appropriate.
Depending on patient age, body weight, symptoms, route and frequency of administration and other factors, the daily dose of these preparations is normally 0.1 to 100 mg/kg, preferably 1 to 50 mg/kg, and more preferably 1 to 10 mg/kg, based on daily dose of active ingredient (Compound (I) or a salt thereof), once or in two portions daily for each asthmatic adult.
The present invention is hereinafter described in more detail by means of the following reference examples, working examples (Examples), formulation examples and experimental examples, which are not to be construed as limitative.